The work proposed is based on the principal investigator's previous studies in connection with this Program Project and recent preliminary data obtained related to the progression of vascular dysfunction during the aging process. Our results allowed us to conclude that the vascular dysfunction observed with aging, is characterized by a progressive reduction in the synthesis and/or bioavailability of nitric oxide (NO), resulting in or caused by an increased oxidant stress in endothelial cells. Significant differences in the regulation by endothelial mediators of skeletal muscle and coronary vessel function were also found in endothelial nitric oxide synthase knockout (eNOS-KO) mice as well as type 2 diabetic (db/db) mice. The aim of our work proposed is to evaluate to what extent the effects of aging of blood vessels is accelerated with cardiovascular disorders and whether aging of blood vessels may provide an additional risk factor for adverse cardiovascular events. These issues will be studied in two models of metabolic syndrome of different etiology, namely type 2 diabetic mice and eNOS.KO mice. In this project we plan to test the hypothesis that the effects of NADPH oxidase-derived oxidants, superoxide and hydrogen peroxide, and their interactions with nitric oxide, on the function of coronary and skeletal muscle resistance vessels during the process of aging, is the primary cause of the development of vascular dysfunction. Specific Aim 1 is to investigate altered mediation of responses to dilator and constrictor agents, pressure and flow of resistance vessels with aging. Specific Aim 2 is to study the progression of metabolic syndrome with aging. These studies will involve measurements of metabolic and hormonal parameters, as well as gene expression in blood vessels during aging. Finally in Specific Aim 3 we aim to elucidate the role of reactive oxidant species on altered regulation of blood vessels with aging, as well as localization of oxidants by state-of-the-art imaging methods. These studies will lead to a better understanding of the causes of age related vascular dysfunction and the pathogenesis of metabolic syndrome, suggesting novel therapeutic targets for the prevention or treatment of these conditions.